Project Summary Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery and is considered as one of the most cost-effective interventions. Although cataract surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the vision care expense by 50%. In addition, our preliminary data supports the hypothesis that an FDA approved drug, tolcapone (CAP1160) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. Therefore, the goal of our proposal is to advance the prodrug of CAP1160, CAP4196 through in vivo efficacy and proof of concept studies to develop a cost-effective non-surgical treatment to: (i) delay the need for cataract surgery and (ii) reduce the disparity of cataract-related blindness globally, and the specific aims are: Aim 1a. Design and synthesis of prodrugs of CAP1160, formulation, stability and maximum tolerated dose (MTD). Aim 1b. Establish cGMP manufacturing and formulation of lead candidate prodrug CAP4196. Aim 2a. Ocular pharmacokinetics of CAP4196. Aim 2b. In vivo POC and efficacy of CAP4196 in dogs with age-related cataracts. Aim 3. SAR based hit-to-lead optimization of naphthalene series from ex vivo efficacy through in vivo safety. Project milestone: Successful completion of these aims will enable CAP4196 to be advanced into clinical development.